The upregulation of most 14-3-3 proteins that is associated with many human tumors including head and neck, and lung tumors suggests contributions of prosurvival and promitogenic functions leading to tumorigenesis. Interestingly, the downregulation of one 14-3-3 family member, 14-3-3 sigma, has been associated with a multitude of human tumors including breast, bladder, and colon. This downregulation of 14-3-3 sigma in breast carcinomas suggests a unique negative/tumor suppressive role for this isoform. This proposal is designed to examine the molecular mechanisms involving 14-3-3 family members (especially sigma) during breast carcinogenesis. I hypothesize that 14-3-3 sigma plays a unique role (as compared to other related 14-3-3 family members) during the G2/M checkpoint and during cellular senescence. A proteomics approach is proposed for identifying novel 14-3-3 sigma-interacting proteins during the development of breast carcinogenesis. In addition, this proposed proteomics approach will give insight into post translational modifications on 14-3-3 sigma following exposure to ionizing radiation. Biological and biochemical analyses will provide significance to the interactions and modifications discovered. The results from this proposal will identify potential future targets for specific anti-cancer therapies.